The "Rogue" Biologist Speaks His Mind

By Cliff Mintz

Synthetic biology is one of the hottest and most rapidly growing new fields in life sciences. While still largely ill-defined, synthetic biology is generally described as the application of the principles of molecular engineering to rationally and systematically construct unique molecules or forms of life with desired properties or characteristics.

The growing popularity of synthetic biology has been fueled by recent advances in DNA-sequencing technologies, genetic engineering, and systems biology. The advent of inexpensive DNA synthesis methodology allows scientists to easily and cost-effectively synthesize large DNA fragments such as entire viral and bacterial genomes. Further, innovations in DNA sequencing, including faster and more powerful DNA sequencing machines and improved computer software algorithms, allow entire genomes to be quickly sequenced, inexpensively deciphered, and ultimately mined for pertinent genetic information. Finally, well-characterized and standardized discrete genetic modules, sometimes referred to as “biobricks,” are being synthesized, which, when rationally and strategically combined (using traditional molecular biological techniques), can yield molecules or cells with completely new biological functions. Together, these advances have laid the groundwork that will likely propel synthetic biology to the forefront of modern drug discovery.

One person who is doing his best to push the current boundaries of synthetic biology to its limits is J. Craig Venter, Ph.D. Last year, Venter and his team at the J. Craig Venter Institute (JCVI) published a groundbreaking paper that heralded the creation of the first completely synthetic bacterium. Starting with a digitized sequence of a bacterium, JCVI scientists synthesized its entire 1.08 megabase pair chromosome, introduced it into recipient bacterial cells, and created bacteria exclusively controlled by the synthetic genome. Although it took Venter and his team of 20 people roughly $40 million and 10 years to accomplish this unprecedented feat, it is the first real demonstration that proves synthetic biology can be used to create so-called novel new life forms or “artificial life.”

Often vilified and considered by many as a “rogue” biologist, Venter first gained international notoriety in 1998 by publicly asserting that his team at Celera Genomics (a company he cofounded) could decode the human genome more quickly than the international public Human Genome Project consortium that was originally assembled to do the work in 1990. After a very public and often acrimonious dispute, Venter and the international consortium agreed to share human DNA sequencing data to complete the project in a timely fashion. With Venter’s help, the Human Genome Project was completed in 2000, three years earlier than the original date set by the international consortium.

After leaving Celera Genomics in 2002, Venter shifted his focus and decided to evaluate the global impact of the genetic diversity of marine microbial communities on natural geobiochemical and environmental processes. This resulted in formation of the Global Ocean Sampling Expedition in the mid-2000s. Microbial samples were obtained by Venter and his team while they circumnavigated the globe on Venter’s 65-foot yacht, Sorcerer II. In between his sailing expeditions, in 2005, Venter cofounded a company called Structural Genomics. The mission of the company is to use genetically modified organisms to produce nonoil-based fuels and other chemicals. Two years ago, ExxonMobil announced a $600 million deal with Structural Genomics to develop so-called “next generation, clean” biofuels.

Formed by Venter in 2006, the JCVI, a not-for-profit genomics research institute, employs more than 400 people and focuses on research involving synthetic biology, genomic medicine, and environmental genomic analysis. Venter is an author of more than 200 scientific papers and the recipient of numerous awards, including the 2001 Paul Ehrlich Award, the Ludwig Darmstaedter Prize and more recently in 2009 the National Medal of Science. He is also a member of the National Academy of Sciences, the American Academy of Arts and Sciences, and the American Society for Microbiology.

I had an opportunity to catch up with Venter (in between trips to the Middle East and Brazil) to discuss synthetic biology, its implications for the future, and his often misunderstood and unconventional approach to life sciences research.

Synthetic Biology Appears To Be The New Buzzword In The Life Sciences Industry. What Exactly Is Synthetic Biology, And Why Is Everyone So Excited About It?
Unfortunately, the term synthetic biology is routinely being misused by many as a catchall term. And, the problem with catchall terms is that they don’t mean anything in the long run. At this point, I think synthetic biology resembles something analogous to a garbage can, that is, a place where people dispose of their garbage, don’t sort it, and almost everything fits! As far as I am concerned, it is not clear whether or not synthetic biology is even a field yet.

What many are trying to pass off as synthetic biology really isn’t much different from what has been going on in molecular biology for the past 30 years. However, on the other end of the spectrum is something we call synthetic genomics. This approach starts with a digitized DNA code on a computer, in vitro synthesis of the DNA sequences that correspond to the code, and then modification and rearrangement of the DNA fragments to create new life forms that do what we want them to do.
Companies like DNA 2.0, GeneArt, and Blue Heron are very good at synthesizing DNA oligonucleotides and rearranging them to yield genes with new functionalities. However, at Synthetic Genomics, we are more interested in synthesizing and building entire genomes or major metabolic pathways rather than synthesizing one gene at a time, which is what most of the synthetic biology business out there presently is trying to do.

In between standard molecular biology and synthetic genomics, I believe there is a lot of exciting and innovative work going on in synthetic biology. For example, several groups have successfully created novel biological on/off switches and rheostats with the goal of creating a biological equivalent of electronic components for building biological circuits. That is what I consider to be true synthetic biology: using biology in a very different way than it has ever been used before.

Which Sectors Of The Life Sciences Industry Are Likely To Benefit The Most From Synthetic Biology?
If we substitute synthetic biology with the phrase “synthetic genomics,” then I think vaccine makers may be the first to benefit. To that end, we recently formed a synthetic genomic vaccine company (working with Novartis) to develop improved flu vaccines. Also, the JCVI is one of the major centers for sequencing the genomes of flu viral isolates from around the world, and we are tracking influenza on a daily basis. Our goal is to help WHO make earlier decisions about annual influenza vaccines based on the influenza genome sequencing data we routinely collect. Further, the institute has received funding from the National Institutes of Health to synthetically make DNA segments of all the thousands of flu viruses that have ever existed and been isolated.

The goal of this project is to preassemble flu genome building blocks in advance and then literally take them off the shelves to create flu variants (that may have never previously existed in nature) to develop multivalent or derivative flu vaccines that offer protection against influenza infection. This approach may allow us to concoct an influenza vaccine candidate in a day or less and substantially reduce morbidity and mortality in an upcoming flu season. I think within the next one to three years people will be immunized with flu vaccines that have been created by synthetic genomic technologies.

As far as biopharmaceutical drug development is concerned, it is reasonable to assume it will take much longer for synthetic genomics to be embraced by industry. This is because of the regulatory hurdles that must be overcome when novel technologies are used to create new drugs. However, in the near term, some of the first therapeutics to benefit from synthetic biology will likely be monoclonal antibody-based products. Synthetic biology is already being used to increase the antigenic repertoire of a variety of monoclonal antibodies. This, in turn, should yield some novel new molecules that ultimately may be turned into new therapeutics.

On a somewhat unrelated front, we are working closely with ExxonMobil to use our synthetic DNA technologies to synthetically create algae that can convert carbon dioxide into various chemicals. I think we will realize success in this field in the next 10 years or so. As I have publicly stated many times in the past, I don’t think there is a single industry that involves biology that won’t in the future benefit or be dominated by synthetic genomic technologies.

Do You Think Personalized Medicine Is Truly Ready For Clinical And Diagnostic Applications? If So, What Role Will Synthetic Biology Play In Its Evolution?
As far as I am concerned, we are not even close to being in the so-called “era of personalized medicine.” And, by way of an analogy, here’s why. Early on, while the Human Genome Project was in progress, everyone thought gene therapy was going to be the miracle cure for all inherited genetic diseases. I argued gene therapy was a great idea — if humans were giant single-cell amoeba. Gene therapy didn’t pan out because many scientists chose to forget basic biology; that is, humans contain over 100 trillion cells. And, getting the right genes, in the right cells, at the right time, with the right genetic regulation is an extremely difficult or near impossible thing to do.

To me, personalized medicine is another one of those fads that is clearly hopeful and forward-looking. But, we are a long way away from realizing its full potential. This is mainly because we don’t know how to correctly interpret the human genome yet. The challenge is to better understand the relationship between the human genotype and corresponding phenotypes. That may require fully sequencing another 10,000 genomes before we are able to begin to compare things and accurately diagnose disease or predict health outcomes based on the genetic code. As a scientist, I think human DNA sequence data needs to be independently validated many times before it can be correctly used in a clinically or medically meaningful way.

There is no question genomic companies like 23 and Me and Navigenics are doing good stuff. But, at this point, they are not much more than interesting tools that permit us to learn a bit more about genomics, genetics, and human ancestry. Unfortunately, DNA sequencing just isn’t accurate enough yet for it to be used for diagnostic purposes or making clinically meaningful decisions. The problem is that, right now, many scientists are overinterpreting what little genomic data we have and overpromising the virtues of personalized medicine.

While we are on the right track, I think we have a long way to go — perhaps a decade or more — before personalized medicine will become a useful technology. I am hopeful and optimistic we can successfully resolve current DNA sequencing accuracy problems and then learn how to intelligently interpret human genomic data. But, we are simply not there yet!

What Qualities Empower You To Push Forward Despite Warnings And Predictions Of Failure?
Sometimes when you look at the size or scale of a problem from the outside, it looks insurmountable or impossible. But, if you immerse yourself in day-to-day operations and the data that is generated from those activities, it becomes much easier to understand where innovation may be necessary to solve the problem. Once this happens, the project seems much less daunting, and it becomes much more manageable and even doable.

For a long time I was a “minority of one” regarding the methods I proposed to sequence and analyze the human genome. It took a lot of convincing and several breakthroughs and contributions by team members like Ham Smith (DNA sequencing technology), Gene Myers and Granger Sutton (algorithms), and Mark Adams (automation) to prove to others it could be done. At the outset of the project, I knew it was theoretically possible, but I also realized I had to assemble a team of experts to be successful. I knew I simply couldn’t do it by myself. And, in retrospect, if I was left on my own, I have no doubt we would still be working on the Human Genome Project today.

I think the reason why scientists are often willing to quickly, and sometimes harshly, criticize people who propose radical new ideas, is that the science community, by its very nature, is extremely conservative. And, I believe the onus is rightly on people like me (who propose radical ideas) to go the extra mile to prove to others the new ideas are valid. That said, I don’t object to the scientific rigor that must be applied to convince others. But, what is troubling is the closemindedness and willingness of detractors to summarily reject anything that is different from what they think is right. I guess this is human nature, and since science is a human endeavor, you can’t expect scientists to be much different from other people.

For me, the good news is that even my harshest critics ultimately adopted my methodology, some with grudging acceptance and others with no acknowledgement at all. In the end, it really doesn’t matter; when something is right in science, then ideas change, and things tend to move forward.

On a personal level, I am not exactly sure what drives me to do things others say I can’t. It’s really a belief in the idea and confidence I can assemble the right team to get the job done. In science, everything is knowledge-based, and the teams I have been lucky to assemble usually have had the best knowledge in the fields we work in. None of the projects I have worked on over the course of my career ever seemed that risky to me! But, maybe they did to others.

By way of analogy, I have sailed across many oceans and experienced some really rough weather. I am confident and comfortable sailing in rough weather — it doesn’t seem that risky to me. But, on the other hand, if you have never been to sea before, then it isn’t a good idea to go to sea during a major storm. The bottom line is, you have to have a healthy dose of self-confidence to succeed in science or any other field. If you don’t believe in yourself, then you can’t expect others to believe in you. I tend to push scientific boundaries because I am a scientist, and scientists love to push boundaries.

Many Government Officials And Business Leaders Contend America Is Losing Its Global Edge In Competitiveness And Innovation. What Are Your Thoughts?
I think the United States is still the best environment in the world for entrepreneurs and science innovators to survive and ultimately thrive. However, American science education is under assault by religious fundamentalism that is threatening to set education agendas in our schools. If we can’t protect American science from assault by religious fundamentalists, then I fear we are very quickly going to lose out to other countries like China, India, or Korea and ultimately become a minor player on the world stage.

Another thing that hurt the United States was the immigration policies of the Bush administration. These policies didn’t allow some of world’s best and brightest students to study in the United States or remain here after completion of their training. Also, the American public’s understanding of science needs to be vastly improved in order for us to be competitive. A good example of this is the recent controversy over the relationship between childhood vaccination and autism. Despite the fact that a link between childhood vaccination and autism was fabricated and is patently false, many Americans still continue to believe there is a link. If Americans continue to place their religious or personal beliefs before evidence-based knowledge or decision making, then I believe the United States is truly doomed as a nation.

Finally, while “science is science” no matter who does it or where it is done, I don’t want to see the United States lose its current leadership role in the life sciences. The proudest moment in my career was when I received the National Medal of Science last year from President Obama. It will truly be a sad day for all Americans if the United States continues to falter and relinquishes its lead in the life sciences.